Project Summary/Abstract This proposal will enable advancement of my research career under the guidance, experience, and tutelage of successful and effective mentors. In addition, my research knowledge will be augmented by training in human studies, animal work and the complex metabolic analytical skills. This proposal will give me the tools necessary to become an independent investigator. Finally, the proposed study provides me the opportunity to continue my current research endeavors, specifically looking at kidney stone disease, endogenous oxalate synthesis, and the role of obesity. The prevalence of kidney stone disease linearly increased in the U.S. over the last several decades, now afflicting 10-15% of the population. The etiology of kidney stone disease is multifactorial involving lifestyle factors, genetics, diet, and environment. Multiple medical comorbidities have been linked to kidney stone disease including obesity. One component of the most common type of stone composition is oxalate, an end product of metabolism. Small increases in urinary oxalate can increase calcium oxalate crystal formation and thus stone disease. Multiple epidemiological studies have demonstrated a positive correlation between obesity and urinary oxalate excretion. Yet, little is known about the underlying reason for this increase in urinary oxalate. Urinary oxalate levels are affected by both a dietary and endogenous component and each is felt to contribute equally. Endogenous oxalate synthesis has been previously thought to occur primarily in the liver and its major source is glyoxylate. The biochemical pathways involved in oxalate production are poorly understood despite extensive research. The central hypothesis is that the increase in urinary oxalate seen in obesity is derived from increased endogenous production. Further, it is proposed that obesity influences the metabolic processes within the liver, resulting in increased oxalate synthesis. The hypotheses will be tested by pursuing two specific aims: 1) Evaluating oxalate synthesis in a lean and a diet-induced obese animal model, 2) To demonstrate that obese humans have increased endogenous oxalate synthesis on controlled diets. I will apply our laboratories expertise in controlled dietary studies in both humans and mice, and utilize complex analytical technologies, including mass spectrometry based assays. The proposed study may provide new insights regarding the role of obesity and fat distribution on endogenous oxalate production and thus calcium oxalate kidney stone disease. It will facilitate my transition into an independent and productive NIH funded investigator.